Study on the reactivity of aldehydes in electrolyzed ionic liquids: Benzoin condensation - Volatile organic compounds (VOCs) vs. room temperature ionic liquids (RTILs)

Article abstract of DOI:10.1002/adsc.201000555

The benzoin condensation of aromatic and heteroaromatic aldehydes, catalyzed by electrochemically generated N-heterocyclic carbenes, has been set up in the absence of organic solvents and bases. α-Hydroxy ketones have been isolated in good to elevated yields, in short reaction times. Aldol products and carbene-aldehyde adducts have been obtained in elevated yields from linear and short branched aldehydes, respectively. A comparison with the use of classical organic solvents has been reported Copyright

Full text of DOI:10.1002/adsc.201000555

FULL PAPERS
DOI: 10.1002/adsc.201000555
Study on the Reactivity of Aldehydes in Electrolyzed Ionic
Liquids: Benzoin Condensation – Volatile Organic Compounds
(VOCs) vs. Room Temperature Ionic Liquids (RTILs)
I. Chiarotto,a,* M. Feroci,a M. Orsini,b M. M. M. Feeney,a and A. Inesia,*
a
Dipartimento di Scienze di Base e Applicate per l’Ingegneria, via Castro Laurenziano, 7, 00161 Roma, Italy
Fax : (+39)-06-4976-6749; e-mail: isabella.chiarotto@uniroma1.it or achille.inesi@uniroma1.it
Dipartimento di Elettronica Applicata, Universitꢀ di Roma Tre, via Vasca Navale, 84, I-00146 Roma, Italy
b
Received: July 14, 2010; Revised: October 7, 2010; Published online: December 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000555.
Abstract: The benzoin condensation of aromatic and tained in elevated yields from linear and short
heteroaromatic aldehydes, catalyzed by electrochem- branched aldehydes, respectively. A comparison with
ically generated N-heterocyclic carbenes, has been the use of classical organic solvents has been report-
set up in the absence of organic solvents and bases. ed
a-Hydroxy ketones have been isolated in good to
elevated yields, in short reaction times. Aldol prod- Keywords: benzoin condensation; electrochemistry;
ucts and carbene-aldehyde adducts have been ob- ionic liquids; N-heterocyclic carbenes
Introduction
volatile solvents (VOCs); in fact, N-heterocyclic car-
benes (imidazol-2-ylidenes or triazol-2-ylidenes) may
In the last years N-heterocyclic carbenes (NHCs: thi- be generated by deprotonation at the C-2 carbon
azolylidene, imidazolylidene, triazolylidene, etc.) have atom of the corresponding salts.
received considerable attention as versatile organoca- Recently, the self condensation of aldehydes has
ACHTUNGTRENNUNG
talysts in a wide range of organic transformations been achieved in water (N,N’-dialkylbenzimidazolium
(benzoin condensation, Stetter reaction, transesterifi- salts as catalysts, Et3N as base, 20 h)[5], in CH2Cl2
cation and acylation reaction, generation of homoeno- (N,N’-dialkylimidazolium salt as catalyst, K2CO3 as
lates, etc.).[1]
base, 12–20 h)[6], or in 1-octyl-3-methylimidazolium
Since the first investigation of Wohler and Liebig,[2] salt as solvent/precatalyst (sodium methoxide as base
concerning the cyanide-catalyzed coupling of benzal- under microwave irradiation).[7]
dehyde to its diphenyl acyloin, the benzoin condensa-
Generally, the deprotonation of the azolium salt is
tion (due to its large use in the carbon-carbon bond carried out in organic solvents (THF, MeCN, CH2Cl2,
formation and in the creation of a stereogenic center) EtOH etc.) in the presence of a base (NaH, KH,
has been extensively investigated. In 1943 the benzoin Et3N, t-BuOK, DBU, NaOH, K2CO3 etc). Some prob-
condensation catalyzed by a thiazolium salt was re- lems related to these procedures (solubility of KH
ported by Ukai et al.[3] The mechanistic model for the and NaH, selectivity, etc.) have been emphasized.[8]
thiazolium salt-catalyzed benzoin condensation was
proposed by Breslow and subsequently studied in electrochemical procedure, able to produce N-hetero-
depth.[1a,4]
cyclic carbenes in the absence of bases as well of
In the last years, we have reported an alternative
According to Breslowꢁs hypothesis, the catalytic VOCs.[9] 1-Butyl-3-methylimidazol-2-ylidene has been
species (the umpolung catalyst) is a heterocyclic car- obtained by cathodic reduction of 1-butyl-3-methyl-
bene (thiazolin-2-ylidene) obtained via deprotonation, imidazolium cation. The procedure was carried out
in the C-2 position, of a thiazolium salt. Afterwards, it via electrolysis of 1-butyl-3-methyl-1H-imidazolium
has been proved that, in addition to thiazolium salts, tetrafluoroborate (Bmim·BF4, that is, a room temper-
a wide variety of heteroazolium salts (imidazolium, ature ionic liquid, RTIL) without the use of any bases
triazolium etc.) are able to catalyze (in the presence or reducing agents and in the total absence of classic
of bases) the benzoin condensation in conventional
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Scheme 1. Benzaldehyde condensation under electrochemi-
cal conditions.
Figure 1. Ionic liquids used as precatalysts.
solvents and it was extended to other 1,3-dialkylimi- sides in the different experimental conditions which
dazolium salts .[10]
can be set up using each of them. In fact, Bhmt·Cl is
In a preliminary investigation on benzaldehyde not a liquid at room temperature (being solid up to
condensation, we have found that the 2-hydroxy-1,2- 858C), so it cannot be used as solvent, but its reduc-
(diphenyl)ethanone (Scheme 1) was obtained by a tion potential is appreciably less negative than that of
catalytic amount of electrochemically generated N- Bmim·BF4, allowing us to reduce considerably the
heterocyclic carbene in 1,3-dialkylimidazolium-based energy consumption when working in VOCs. On the
ionic liquids in good yield and short time (2 h).[11] other hand, it can behave both as a supporting elec-
This result prompted us to investigate more extensive- trolyte and precatalyst, avoiding the use of other salts.
ly this new electrochemical methodology of genera-
tion of carbene and its application to the benzoin con- use it as solvent-supporting electrolyte-precatalyst,
densation. being so the only species necessary in the elctrolytic
Bmim·BF4 is an RTIL, and this feature allows us to
The aims of this investigation were: (i) to compare cell. Its drawback is the more negative reduction po-
the reactivity of benzaldehyde in the presence of N- tential that, along with the energy consumption, pre-
heterocyclic carbenes electrogenerated in ionic liquids vents in some cases, its use in VOCs.
or in classical organic solvents and (ii) to demonstrate
In both cases, the monoelectronic electrochemical
the feasibility of this alternative simple and green reduction of the precatalyst led to the formation of
electrochemical methodology for the synthesis of a- the corresponding carbene and molecular hydrogen
hydroxy ketones (via benzoin condensation) using the [Scheme 2, Eq. (1)].
“green” electron as base and RTILs both as solvent-
supporting electrolyte system and as precatalyst.
The benzoin reaction of benzaldehyde 3a
[Scheme 2, Eq. (2)] was therefore accomplished fol-
Benzoin is an a-hydroxy ketone; the a-hydroxy car- lowing two different procedures, using VOCs (Proce-
bonyl group is an important synthon for the synthesis dure A) or using RTIL (Procedure B).
of natural products, chiral auxiliaries and ligands. In
In the Procedure A, solutions of VOCs containing
fact, it is the starting material for the synthesis of Bmim·BF4 1 or Bhmt·Cl 2 were electrolyzed, under
2,3,5-substituted tetrahydrofurans (cancer chemopre- N2 at room temperature, in a divided cell (Pt as cath-
ventives[12] and selective COX-Z inhibitors[13]) of 4,5- ode and anode) under galvanostatic conditions. The
diarylimidaxoles (human CB1 receptor inverse ago- electrolyses were stopped according to the consump-
nists),[14] of 3,4,5-triaryl-1H-pyrroles (antihyperglyce- tion at the electrodes of 0.2 Faradays per mole of al-
mic molecules),[15] etc. Moreover, some substituted dehyde (10 mmol), subsequently added to the catho-
benzoins have themselves pharmacological activities. dic compartment. The cathodic solutions were stirred
For exemple, some fluorobenzoins are inhibitors of
mammalian carboxylesterases,[16] while various a-hy-
droxy ketones are inhibitors of urease.[17] The impor-
tance of this class of compounds, therefore, has spur-
red the scientific community to elaborate new and ef-
ficient synthetic methodologies.
Results and Discussion
We have approached the task of comparison of the
reactivity of NHCs versus benzaldehyde in different
media (VOCs or RTILs) by choosing two different
precatalysts:
1-butyl-3-methyl-imidazolium
tetrafluoroborate (Bmim·BF4) 1 and 3-benzyl-5-(2-hy-
ACHTUNGTRENNUNG
droxyethyl)-4-methylthyazolium cloride (Bhmt·Cl) 2
(Figure 1). The choice of these two precatalysts re- Scheme 2. General scheme for the reaction.
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Study on the Reactivity of Aldehydes in Electrolyzed Ionic Liquids: Benzoin Condensation
Table 1. Reactivity of benzaldehyde 3a in electrolyzed solu-
tions of Bmim·BF4 1 or Bhmt·Cl 2 in VOCs (Procedure A)
or in electrolyzed solutions of Bmim·BF4 (Procedure B).
Benzoin condensation.
fact, both 1 and 2 in solution (DMSO, MeCN, DMF
as solvents) can be cathodically reduced to carbene;
however, 2 is more easily reduced with respect to 1,
that is, at a more positive potential. In fact, the vol-
tammetric curves recorded for solutions of 1 and 2 in
DMSO show a reduction peak at Ep=À2.55 V and
Ep=À1.63 V respectively (C cathode; v=0.20 VsÀ1;
c=5 10À3 mol dmÀ3; room temperature).[18] Accord-
ingly, the selective cathodic reduction of 1 in solution
may be hard to set up, if compared with that of 2.
Therefore, we have contemplated to electrolyze the
salt 1 (liquid at room temperature) in the absence of
any solvent (Procedure B). In these conditions, after
the consumption of 0.2 Faraday molÀ1 of benzalde-
hyde 3a, subsequently added to the electrolyzed salt
1, benzoin 4a was isolated in elevated yield (85%
Table 1, entry 8).
Entry Procedure VOC
Precatalyst Q[a] Yield 4a[b]
1
2
A
A
A
A
A
A
A
B
DMSO
MeCN
DMF
DMF
DMF
DMF
DMF
–
2
2
2
2
1
1
1
1
0.2 45%
0.2 70%
0.2 75%
0.2 64%
0.2 traces
1.0 12%
2.0 30%
0.2 85%
3
4[c]
5
6
7
8[d]
[a]
Number of Faradays per mol of 3a supplied to the elec-
trodes.
[b]
[c]
Isolated yields with respect to starting benzaldehyde.
Et4N·BF4 (0.1 moldmÀ3) was used as supporting electro-
lyte.
Having completed the first of our objectives, that is,
the comparison of the usual electroorganic conditions
and the use of an RTIL in the organocatalyzed ben-
zoin condensation, with a clear superiority of the
ionic liquid medium, we have examined the second
[d]
This entry was reported in ref.[11], carried out under the
best experimental conditions.
at 658C for 2.0 h and their work-up provided the cor- part, studying the versatility of this methodology. We
responding products. In this procedure, 1 and 2 play have thus investigated the reactivity of several aro-
both the roles of supporting electrolytes and precata- matic, heteroaromatic and aliphatic aldehydes (3b–n)
lysts.
following Procedure B (20% organocatalyst with re-
In the Procedure B, the ionic liquid Bmim·BF4 1 spect to aldehyde). The results have been summarized
was electrolyzed in the absence of any solvent. Subse- in Table 2.
quently, this procedure was performed in the same
way as procedure A. Accordingly, 1 plays the roles of dehydes furnished the corresponding a-hydroxy ke-
solvent, supporting elecrolyte and precatalyst. tones (Table 2, entries 1–8). The yields of isolated
Aromatic (3a–f) and heteroaromatic (3g and h) al-
In Table 1 the results obtained following Procedure products (from very high, 92%, to moderate, 32%)
A with benzaldehyde are reported. At first, our are strongly affected by the nature of the substituent
choice was precatalyst 2 (due to its less negative re- on the aromatic nucleus.
duction potential), electrolyzed in DMSO, MeCN and
In agreement with the mechanism proposed by Bre-
DMF (solvents currently used in electroorganic syn- slow[4] and subsequently reported by other authors[1a]
,
thesis). The electrolyses were stopped after the theo- the NHC-catalyzed benzoin condensation may be
retical generation of 20% of organocatalyst (with re- summarized as shown in Scheme 3.
spect to benzaldehyde). The number of Faradays was
The cathodic monoelectronic reduction of imidazo-
evaluated and prefixed assuming unitary as the cur- lium cation 1 gives imidazolium-2-ylidene 1a, which
rent yield. The yields of benzoin 4a, isolated from the adds to aldehyde 3 yielding the Breslow intermediate
cathodic solution were strongly affected by the nature 6 via the adduct 5. The Breslow nucleophilic inter-
of the solvent (Table 1, entries 1–3). To confirm the mediate 6 is able to add to a second molecule of 3 af-
effective role of supporting electrolyte played by 2 fording 7, which eliminates the a-hydroxy ketone 4,
(besides being a precatalyst), the addition of a partic- regenerating carbene 1a. However, competitive reac-
ular, classical supporting electrolyte (tetraethylammo- tions, such as the protonation of 5 (see later), could
nium tetrafluoroborate, Et4N·BF4) to the solution, affect the yield of 4.
before the electrolysis, does not increase the efficien-
cy of the procedure (Table 1, entry 4).
As previously reported by other authors[5] (reaction
carried out in water or in organic solvents, imidazoli-
Surprisingly, if 1 (instead of 2) was used as support- um salts and bases as precatalysts), no a-hydroxy ke-
ing electrolyte-precatalyst in DMF, the efficiency of tones have been isolated in the case of aldehydes pos-
the procedure decreased dramatically, also in spite of sessing a strong electron-donating or electon-with-
the consumption of a greater number of Faradays; in drawing group (3i and 3j, respectively, Table 2, en-
fact, the yields of isolated 4a were only low, 12–30% tries 9 and 10).
(Table 1, entries 5–7).
This drawback may be related to the different volt- same reaction conditions, give the aldol condensation.
ACHTUNGTRENNUNGammetric behaviour of solutions containing 1 or 2. In The presence of an a-hydrogen to the carbonyl group
Linear aliphatic aldehydes 3m and 3n, under the
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I. Chiarotto et al.
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Table 2. Reactivity of aldehydes 3a–n in electrolyzed solu-
tions of Bmim·BF4 1 (Procedure B).
Scheme 3. Mechanism proposed for the NHC-catalyzed ben-
zoin condensation.
of imidazolium salts/bases precatalysts in VOCs,
afford aldol condensation instead of benzoin conden-
sation.[6] Nevertheless, a single example of benzoin
condensation, with octanal in the presence of benzyli-
midazolium salts/DBU as precatalysts in DMF, has
been recently reported.[19]
The behaviour of a-branched aliphatic aldehydes is
different from those of both linear aliphatic and aro-
matic aldehydes. Isobutyraldehyde 3k and cyclohex-
AHCTUNGTREGUNaNN necarbaldehyde 3l, under the same experimental
conditions, yield exclusively an adduct with the elec-
trogenerated carbene (5’k and 5’l, Table 2, entries 11
and 12) in high yields. These adducts derive from the
protonation of the zwitterionic intermediate
5
(Scheme 3); in fact, these two a-branched aliphatic al-
dehydes cannot undergo aldol condensation and the
aldol reaction is not active, as well as the benzoin
condensation. This is probably due to the too low
À
acidity of the C H that links the oxygen anion in in-
termediate 5 (Scheme 3) with respect to the C H in
À
the 2-position of the imidazolium cation. In fact, the
elevated yields of isolated 5’k and 5’l (90 and 77%),
with respect to the consumption of 0.2 FmolÀ1 of al-
dehyde (i.e., the presence of carbene in 20% molar
ratio with aldehyde) suggests one to consider this re-
[a]
Isolated yields with respect to starting aldehyde.
This entry was reported in Table 1 entry 1.
[b]
allows the NHC to act solely as a base and the loss of action as an autocatalytic protonation (Scheme 4).
a molecule of water yields the a,b-unsaturated prod- Adducts 5’k and 5’l are stable (they have been iso-
ucts 8m and 8n (95 and 70%, respectively; Table 2, lated by column flash chromatography) and they are
entries 13 and 14). This result is not unexpected; in themselves ionic liquids. To the best of our knowl-
fact, in the past it has been emphasized by many au- edge, this is the first time that NHC-aliphatic alde-
thors that linear aliphatic aldehydes, in the presence hyde adducts have been isolated; in fact, the adduct
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Study on the Reactivity of Aldehydes in Electrolyzed Ionic Liquids: Benzoin Condensation
Scheme 4. Reaction of autocatalytic protonation in the formation of NHC-aliphatic aldehyde adducts.
was a Pt spiral (apparent area 1.0 cm2) and the counter elec-
trode a cylindrical platinum gauze (apparent area 0.8 cm2).
derived from the direct addition of a deprotonated
imidazolium salt to benzaldehyde, was first reported
by V. K. Aggarwal[20] in the base-catalyzed Baylis–
Hillman reaction; this side reaction (involving the Typical Procedure for Electrolyses in VOCs
precatalyst) consumes benzaldehyde and can be sig-
Anolyte (2.0 cm3 of VOC, 0.1 moldmÀ3 Et4N·BF4) and cath-
nificant. Recently, K. A. Scheidt and co-workers have
reported that, in the carbene-catalyzed redox reaction
of aldehydes and related processes, a transient benzyl-
ic alcohol intemediate should be accessible through
addition of N-heterocyclic carbene to any aldehyde.[21]
olyte (5.0 cm3 of VOC, 0.1 moldmÀ3 Bmim·BF4) were sepa-
rated through a porous plug filled with methylcellulose in
DMF-Et4N·BF4. The electrolysis was carried out, under a ni-
trogen atmosphere at room temperature, at constant current
(30 mAcmÀ2). The electrolysis was stopped after
194 Coulomb. At the end of the electrolysis, 10 mmol of al-
dehyde 3 were added to the catholyte, the temperature was
increased up to 658C and the mixture was stirred for 2 h.
The reaction mixture was poured into water and then ex-
tracted with diethyl ether (3ꢃ20 cm3). After the removal of
the solvent from the combined ethereal layers under re-
duced pressure, the crude reaction mixture was analyzed by
1H NMR and TLC. The products were purified using flash
chromatography (n-hexane-ethyl acetate, 8:2) and character-
ized by NMR spectroscopy.
Conclusions
The reactivity of aldehydes in the presence of electro-
generated N-heterocyclic carbenes is strongly affected
by the nature of the solvent (RTILs or VOCs) as well
as by the structure of the substrates and precatalysts.
The isolated products may be related to benzoin
condensation, aldol condensation and to the forma-
tion of carbene-aldehyde adducts.
Typical Procedure for Electrolyses in RTIL
By adding aldehydes to electrolyzed Bmim·BF4, in
the absence of any VOCs and bases, aromatic a-hy-
droxy ketones 4a–h have been isolated in good to
very elevated yieds, in a short reaction time (2.0 h);
aldol products 8m and 8n and carbene-aldehyde ad-
ducts 5’k and 5’l have been obtained in elevated
yields from linear 3m and 3n and short branched 3k
and 3l aldehydes, respectively.
Anolyte (1.0 cm3 of ionic liquid) and catholyte (ꢀ2.0 cm3 of
ionic liquid) were separated through a G-4 glass septum.
The electrolysis was carried out, under a nitrogen atmos-
phere at room temperature, at constant current
(30 mAcmÀ2) in 10 mmol of ionic liquid Bmim·BF4. The
electrolysis was stopped after 194 Coulomb. At the end of
the electrolysis, 10 mmol of aldehyde 3 were added to the
catholyte, the temperature was increased up to 658C and
the mixture was stirred for 2 h. The reaction mixture was
then extracted with diethyl ether (3ꢃ10 cm3, leaving under
stirring with diethyl ether for 15 min each time). After the
removal of the solvent from the combined ethereal layers
under reduced pressure, the crude reaction mixture was ana-
lyzed by 1H NMR and TLC.
This is the first time, to the best of our knowledge,
that this kind of adduct between NHCs and aliphatic
aldehydes has been isolated.
Experimental Section
All products were purified using flash chromatography (n-
hexane-ethyl acetate, 8:2) and characterized by NMR spec-
troscopy. All benzoins 4a–h and aldol products 8m and n are
known compounds and their spectral data are in accordance
with those reported in the literature.
Electrolyses under galvanostatic control were carried out
with an Amel 552 potentiostat equipped with an Amel 721
integrator. A two-compartement cell was used; the cathode
Adv. Synth. Catal. 2010, 352, 3287 – 3292
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I. Chiarotto et al.
FULL PAPERS
Sotgiu, I. Chiarotto, M. Feroci, M. Orsini, L. Rossi, A.
Inesi, Electrochim. Acta, 2008, 53, 7852–7858; c) B.
Gorodetsky, T. Ramnial, N. R. Branda, J. A. C. Cly-
burne, Chem. Commun. 2004, 1972–1973; d) L. Xiao,
K. E. Johnson, J. Electrochem. Soc. 2003, 150, 307–311.
[10] I. Chiarotto, M. Feroci, M. Orsini, G. Sotgiu, A. Inesi,
Tetrahedron 2009, 65, 3704–3710.
[11] M. Orsini, I. Chiarotto, M. N. Elinson, G. Sotgiu, A.
Inesi, Electrochem. Commun. 2009, 11, 1013–1017.
[12] P. Singh, A. Mittal, S. Kumar, Bioorg. Med. Chem.
2007, 15, 3990–3996.
Purification of Used RTIL
We have handled the possibility of recycling the cathodic
ionic liquid after the benzoin condensation. As a small
amount of the protonated adduct 5’ (5–10%) remains in the
cathodic RTIL after ethereal extraction, a flash chromatog-
raphy (ethyl acetate as eluent) is necessary to purify it (the
adduct 5’ being a salt itself), so that, the ionic liquid comes
back pure and reusable.[22]
Acknowledgements
[13] P. Singh, A. Mittal, S. Kaur, S. Kumar, Bioorg. Med.
Chem. 2006, 14, 7910–7916.
We thank Marco Di Pilato for his support to the experimental
part and MIUR and CNR (Italy) for financial support.
[14] C. W. Plummer, P. E. Finke, S. G. Mills, J. Wang, X.
Tong, G. A. Doss, T. M. Fong, J. Z. Lao, M.-T. Schaeff-
er, J. Chen, C.-P. Shen, D. Sloan Stribling, L. P. Shear-
man, A. M. Strack, L. H. T. Van der Ploeg, Bioorg.
Med. Chem. Lett. 2005, 15, 1441–1446.
[15] A. Goel, N. Agaewal, F. V. Singh, A. Sharon, P. Tiwari,
M. Dixit, R. Pratap, A. K. Srivastava, P. R. Maulik,
V. J. Ram, Bioorg. Med. Chem. Lett. 2004, 14, 1089–
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